Project Summary Addiction to nicotine through tobacco use is the leading preventable cause of death in the US, contributing to almost half a million deaths per year. There are over 20 diseases associated with smoking include lung cancer, chronic obstructive pulmonary disease, cardiovascular disease, and stroke. Many smokers have the desire to reduce or stop using tobacco;however less then 7% are successful for a year or more. Accumulating evidence suggests that serotonin neurotransmission plays a role in the establishment and maintenance of nicotine addiction. Modified serotonergic neurotransmission is thought to contribute to the rewarding and anxiolytic properties of acute nicotine administration, as well as to symptoms of nicotine withdrawal. Therefore understanding how nicotine acts on serotonergic neurons may give insight into the mechanisms participating in addictive behavior that underlie the negative health impact of tobacco use. The Aims of this proposal are designed to systematically determine how acute and chronic nicotine treatment or nicotine withdrawal influences ascending serotonergic pathways. Neuroanatomical and pharmacological methods in a rat model are used. The hypothesis tested in Aim 1 is that nicotine administration and withdrawal have topographically organized and distinct effects on the ascending raphe. Subsequent Aims investigate the mechanisms underlying these topographic effects. In Aim 2, the role of 5-HT-1A receptors have in contributing to the topographic control of activation of the ascending raphe will be determined. In Aim 3 is test the hypotheses that the differential subcellular distribution of the alpha4 nicotinic receptor subunit could contribute t to the topographically selective effects, and that alpha4 containing receptors shift in subcellular distribution as a consequence of nicotine exposure by using immunolabeling techniques coupled with ultrastructural analysis. A further understanding of how nicotine acts on the ascending serotonergic pathways will give insight into the basic neurochemical changes nicotine produces in the brain that are implicated in addictive behavior. This information will likely have relevance for understanding how serotonin contributes to drug addiction in general.Project Narrative The proposed studies are designed to help understand the neurobiological basis of how nicotine addiction develops and why it often co-occurs with mood disorders. The results may suggest treatment strategies for both of these important health issues.